Summary | Management of CV Risk & T2DM: Implications of novel outcome trials

Diabetes has a tremendous impact on the outcome of patients in CV practice, and therefore on the treatment of these patients. For example, life expectancy is shortened by 6 years in the presence of diabetes. The biggest impact is observed in younger patients from 40 to 60 years old in the study by Seshasai et al.6 The Swedish National Diabetes Register also demonstrated the biggest impact of type 2 diabetes (T2DM) on premature CV mortality in patients <55 years old and 55-64 years old.7 A large epidemiology study has shown that diabetes adds to the risk conferred by other known major CV risk factors, such as cholesterol, BP and smoking.8

In the past decade, clinicians have done very well in reducing glucose-related complications, but less in decreasing CV complications. A review from Gregg et al.9 showed that the number of hyperglycemic deaths since 1988 has declined, however admissions due to CV complications have not decreased to the same extent. Most clinicians have focused on reducing traditional CV risk factors rather than lowering glucose. This can be explained by the impressive impact of BP and cholesterol on CV risk in patients with diabetes, and a much weaker association of CV risk with fasting blood glucose.10 The CARDS trial was the first trial to evaluate the effect of a statin in diabetes patients, which resulted in a lower cumulative hazard for myocardial infarction (MI) and CV death with atorvastatin as compared to placebo and the trial was stopped early due to great success.11 Similar data but to a lesser degree were seen regarding the impact of BP lowering on CV and renal outcomes.12 Altogether, a recent meta-analysis confirmed these results, with disappointing results for traditional glucose lowering on CV risk reduction.13

Empagliflozin showed the best benefit in terms of CV death and HF hospitalization and due to the early benefits, guideline recommendations now already include the use of empagliflozin.

Metformin has long been used by cardiologists in routine clinical practice. Other glucose lowering drugs, however, may be harmful by increasing CV risk. Rosiglitazone for instance was demonstrated to increase the risk of MI and death by CV causes and has therefore been withdrawn from clinical use.14 Other classic glucose lowering drugs, such as sulphonyl ureas, thiazolidinediones, DPP-4 inhibitors, and insulin, might also increase CV risk. As a result, both FDA and EMA have changed the study requirements and they now demand stringent demonstration of CV safety of new diabetes agents. These types of requirements have been applied to the newer approaches in development to reduce blood glucose.

The most recent additions to the therapeutic options in diabetes are the GLP-1 receptor agonists and SGLT2 inhibitors. Although the trials evaluating these drugs were designed to show noninferiority, two drugs showed a possible CV advantage in patients with diabetes and CVD. First, the LEADER trial evaluating the GLP-1 receptor agonist liraglutide showed an overall 13% reduction in hazard of CV endpoints over a 5-year period. Not much benefit was seen in the first year, but progressive benefit was seen up to 5 years.15 Second, treatment with the SGLT2 inhibitor empagliflozin, which inhibits renal reabsorption of blood glucose, in the EMPA-REG OUTCOME trial, resulted in a reduction of almost 40% in CV mortality and 35% HF hospitalization in diabetes patients. The benefit was apparent within a rather short time after start of therapy, which was very different from the pattern seen with liraglutide treatment.16 The finding of the reduction in HF hospitalization with empagliflozin has drawn great interest, as the presentation of patients with diabetes has changed over time from CV events to a large portion of patients now presenting with HF. The drugs tested in the EMPA-REG OUTCOME, LEADER and SUSTAIN-6 (testing the GLP-1 receptor agonist semaglutide) trials all showed a reduction in MI, however, there were differential effects on stroke, which needs further research.17 Empagliflozin showed the best benefit in terms of CV death and HF hospitalization and due to the early benefits, guideline recommendations now already include the use of empagliflozin. Empagliflozin should be considered for patients with T2DM to prevent or delay the onset of HF and to prolong life.

An area of interest in the next few years is the potential opportunity to combine SGLT2 inhibitors and GLP-1 receptor agonists, due to their differential effects on atherosclerosis/atherogenesis as opposed to CV hemodynamics, which may underlie the CV benefits seen with SGLT2 inhibition.17 It will be interesting to see if combining these agents yields incremental benefit in different categories of patients. The unexpected CV benefit from these drugs has raised the question how these drugs work to result in the observed clinical benefit. Also, it will be interesting to examine the benefit of SGLT2 inhibition in patients who do not have diabetes (yet). Two trials are currently being undertaken; dapagliflozin and empagliflozin are tested in the DAPA-HF trial in patients with HF with reduced ejection fraction and the EMPEROR-Preserved trial tests empagliflozin in patients with chronic HF with preserved ejection fraction.

This is a new era for CVD management in diabetes patients; both diabetologists and cardiologists should work together. Besides lowering traditional CV risk factors, patients can also benefit from new diabetes drugs, in particular SGLT2 inhibitors. Future studies will give more insight in broader implications, early treatment, and prevention with this new class of drugs, even in patients who do not have diabetes.

References

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